aki guideline

8/20/2019 AKI guideline

1/24

KDOQI Commentary

KDOQI US Commentary on the 2012 KDIGO Clinical PracticeGuideline for Acute Kidney Injury

Paul M. Palevsky, MD,1,2 Kathleen D. Liu, MD, PhD,3 Patrick D. Brophy, MD,4

Lakhmir S. Chawla, MD,5 Chirag R. Parikh, MD, PhD,6,7 Charuhas V. Thakar, MD,8,9

Ashita J. Tolwani, MD,10 Sushrut S. Waikar, MD,11 and Steven D. Weisbord, MD 1,2

In response to the recently released 2012 KDIGO (Kidney Disease: Improving Global Outcomes) clinical

practice guideline for acute kidney injury (AKI), the National Kidney Foundation organized a group of US

experts in adult and pediatricAKI and critical care nephrology to review the recommendationsand comment on

their relevancy in the context of current US clinical practice and concerns. The first portion of the KDIGO

guideline attempts to harmonize earlier consensus definitions and staging criteria for AKI. While the expert

panel thought that the KDIGO definition and staging criteria are appropriate for defining the epidemiology of

AKI and in the design of clinical trials, the panel concluded that there is insufficient evidence to support their

widespread application to clinical care in the United States. The panel generally concurred with the remainder

of the KDIGO guidelines that are focused on the prevention and pharmacologic and dialytic management of

AKI, although noting the dearth of clinical trial evidence to provide strong evidence-based recommendations

and the continued absence of effective therapies beyond hemodynamic optimization and avoidance of

nephrotoxins for the prevention and treatment of AKI.

Am J Kidney Dis. 61(5):649-672. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.

This is a US Government Work. There are no restrictions on its use.

Editorial, p. 686

INTRODUCTION

KDIGO (Kidney Disease: Improving Global Out-comes) is an international initiative to develop andimplement clinical practice guidelines for patients with

kidney disease. In March 2012, KDIGO published itsguideline for the evaluation and management of acutekidney injury (AKI).1 This guideline covers numeroustopics, including the definition and classification ofAKI,the prevention and treatment of AKI in general withspecific recommendations for the prevention of contrast-induced AKI, and the management of renal replacementtherapy (RRT) in patients with AKI. Because interna-

tional guidelines need to be adapted for the UnitedStates, the National Kidney Foundation–Kidney DiseaseOutcomes Quality Initiative (NKF-KDOQI) convened amultidisciplinary work group with expertise in adult andpediatric nephrology and critical care medicine to com-

ment on the applicability and implementation of theKDIGO AKI guideline in the United States. This com-mentary provides a summary of the KDIGO recommen-

dation statements along with the supporting rationalesand comments on their applicability to clinical practicein the United States. The KDOQI Work Group congratu-lates KDIGO, the members of the AKI Guideline Work Group, and the evidence review team for producing sucha comprehensive document and believes that this guide-line will be of great value to health professionals and willadvance both current clinical care of patients with AKIand future clinical research.

AKI represents the sudden loss of kidney function,

generally occurring over the course of hours to days

and resulting in the retention of metabolic waste

products and dysregulation of fluid, electrolyte, and

acid-base homeostasis. During the past decade, this

acute loss of kidney function, previously referred to as

acute renal failure, has been the subject of significant

re-examination, with increased recognition of the impor-

Originally published online March 18, 2013From the 1 Renal Section, VA Pittsburgh Healthcare System;

2 Renal-Electrolyte Division, Department of Medicine, Universityof Pittsburgh School of Medicine, Pittsburgh, PA; 3 Nephrology Division, Department of Medicine, University of California, SanFrancisco, CA; 4 Nephrology Division, Department of Pediatrics,University of Iowa Carver College of Medicine, Iowa City, IA;5 Department of Anesthesiology and Critical Care Medicine and Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University, Washington, DC; 6 Re-nal Section, VA Connecticut Healthcare System, West Haven;7 Section of Nephrology, Department of Medicine, Yale UniversitySchool of Medicine, New Haven, CT; 8 Renal Section, CincinnatiVA Medical Center; 9 Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati, Cincin-nati, OH; 10 Division of Nephrology, Department of Medicine,University of Alabama at Birmingham, Birmingham, AL; and 11 Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA.

Address correspondence to Paul M. Palevsky, MD, Rm 7E123(111F-U), VA Pittsburgh Healthcare System, University Dr, Pitts-burgh, PA 14240. E-mail: [email protected]

Published by Elsevier Inc. on behalf of the National KidneyFoundation, Inc. This is a US Government Work. There are norestrictions on its use.

0272-6386/$0.00http://dx.doi.org/10.1053/j.ajkd.2013.02.349

Am J Kidney Dis. 2013;61(5):649-672 649

mailto:[email protected]:[email protected]://dx.doi.org/10.1053/j.ajkd.2013.02.349http://dx.doi.org/10.1053/j.ajkd.2013.02.349http://dx.doi.org/10.1053/j.ajkd.2013.02.349mailto:[email protected]


2/24

tance of relatively small changes in kidney function onboth short- and longer term clinical outcomes.2-6 Thishas resulted in the change in terminology from acuterenal failure, for which the focus generally was limitedto the most severe episodes with complete or near-

complete loss of kidney function, to the current terminol-ogy of AKI, with increased focus on smaller decrementsin kidney function.7-9

AKI may develop in a wide variety of settings, includ-ing in ambulatory outpatients, hospitalized patients, and,in particular, critically ill patients, for whom AKI repre-

sents a common complication of both underlying diseaseand treatment. AKI is associated withsubstantial morbid-ity and mortality. For example, severe AKI occurs in

5% of critically ill patients and is associated withmortality rates of 40%-70%.10-12 Although recovery of kidney function occurs in the majority of patients surviv-ing an episode of AKI, many patients remain dialysisdependent or are left with severe renal impairment. Morerecently, it has been recognized that even patients whohave complete or near-complete recovery of kidneyfunction are at increased risk of progressive chronic

kidney disease (CKD) and that superimposition of AKI

on CKD is associated with acceleration in the rate of progression to end-stage disease.13-17

Our understanding of the epidemiology of AKI andinterpretation of results across clinical trials has beenhindered by the prior absence of a broadly accepted

clinical definition, with more than 30 operationaldefinitions of AKI used in published studies.18 Duringthe past decade, there has been a considerable effort toforge a consensus definition. The first attempt atdeveloping a consensus definition, known as theRIFLE criteria, was developed by the Acute Dialysis

Quality Initiative (ADQI) in 2002 (Table 1).19 Thisdefinition considered 3 strata of severity (risk, injury,and failure) based on the magnitude of increase in

serum creatinine level and/or the duration of oliguria,as well as 2 outcome stages (loss of kidney functionand end-stage kidney disease). The risk, injury, andfailure categories were constructed to provide grada-tions in severity of kidney dysfunction, with greatersensitivity associated with risk and greater specificitywith failure. The RIFLE criteria subsequently weremodified by the AKI Network (AKIN) by the addition

of an absolute increase in serum creatinine level 0.3

Table 1. RIFLE and AKIN Criteria for Diagnosis and Classification of AKI

RIFLE

Urine Output

(common to both)

AKIN

Class SCra Stage SCrb

Risk Increased SCr to 1.5 baseline Urine output 0.5 mg/kg/h

for 6 h

1 Increase in SCr 0.3 mg/dL or

increase in SCr to 150%-200% of baseline

Injury Increased SCr to 2 baseline Urine output 0.5 mg/kg/h

for 12 h

2 Increase in SCr to 200%-

300% of baseline

Failure Increased SCr to 3 baseline; or an

increase of 0.5 mg/dL to a value

of 4 mg/dL

Urine output 0.3 mg/kg/h

for 12 h or anuria for

12 h

3 Increase in SCr to 300% of

baseline; or to 4 mg/dL

with an acute increase of

0.5 mg/dL; or on RRT

Loss Need for RRT for 4 wk

End Stage Need for RRT for 3 mo

Abbreviations: AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; RIFLE, risk, injury, failure, loss, end-stage disease; RRT,

renal replacement therapy; SCr, serum creatinine.aFor RIFLE, the increase in SCr should be both abrupt (within 1-7 days) and sustained (24 hours).bFor AKIN, the increase in SCr must occur in less than 48 hours.

Table 2. Pediatric Modified RIFLE (pRIFLE) Criteria for Diagnosis and Classification of AKI in Children

Class eCCr Urine Output

Risk eCCr decrease by 25% Urine output 0.5 mL/kg/h for 8 h

Injury eCCr decrease by 50% Urine output 0.5 mL/kg/h for 16 h

Failure eCCr decrease by75%; or eCCr 35 mL/min/1.73 m2 Urine output 0.3 mL/kg/h for 12 h; or anuria for 12 h

Loss Persistent failure for 4 wk

End Stage Persistent failure for3 mo

Abbreviations and definitions: AKI, acute kidney injury; eCCr: estimated creatinine clearance using the Schwartz formula; RIFLE,

risk, injury, failure, loss, end-stage disease.

Adapted and reproduced from Akcan-Arikan et al,20 with permission of MacMillan Publishers Ltd.

Am J Kidney Dis. 2013;61(5):649-672650

Palevsky et al


3/24

mg/dL to the definition of AKI, a shortening of thetime for the increase in serum creatinine level from 7days to no more than 48 hours, and elimination of the2 outcome criteria (Table 1).7,8 A modification of theRIFLE criteria for use in pediatric patients (pRIFLE)has also been developed (Table 2).20 Validation stud-

ies using these definitions have demonstrated in-creased mortality risk associated with progressivelymore severe stages of AKI. The KDIGO AKI guide-line builds upon these earlier efforts in defining AKI,with a full section of the guideline devoted to thedefinition of AKI.

The development of successful therapeutic strate-gies for the prevention and treatment of most forms of

AKI has been disappointing. Although numerousagents have shown promise in experimental models,none has demonstrated utility in clinical care. Aparticular area of focus has been in the prevention of contrast-induced AKI. This common cause of AKI hasbeen the focus of multiple preventative interventionsbecause individuals at high risk of contrast-inducedAKI can be readily identified and the timing of

exposure can be predetermined, allowing an opportu-nity for intervention. In the absence of effective phar-macologic therapy, the management of establishedAKI is predominantly supportive care, with the use of RRT in severe AKI. There has been tremendousadvancement in the technology and modalities avail-able for providing RRT; however, the optimal ap-proach to management of RRT in this setting remains

controversial. The KDIGO AKI guideline provides

specific recommendations, based on the current litera-ture, for best practices in the prevention and manage-ment of AKI. In this KDOQI commentary, we haveattempted to place this international guideline in thecontext of care practices in the United States. How-ever, our commentary should be viewed in conjunc-tion with the full KDIGO document when makingclinical decisions.

REVIEWANDAPPROVAL PROCESS FOR

THIS COMMENTARY

This commentary was developed by a Work Group

convened by the NKF-KDOQI, beginning with se-lecting Co-Chairs by the KDOQI steering commit-tee and individual members selected based on theirclinical expertise and interest in the guideline pro-cess. Teleconferences took place during 2011 and2012 to determine the specific areas for focus forthis commentary. Individual sections focusing oneach of the topical areas of the KDIGO AKI guide-

line were drafted by groups of coauthors based ondetailed review of the particular KDIGO chaptersupplemented by additional literature review, asneeded. Because this was a commentary, no specific

voting occurred; rather, consensus among coau-

thors was achieved through discussion. The docu-

ment was reviewed and approved by all coauthors

and by the KDOQI leadership.

ASSESSMENT OF GUIDELINEQUALITY

The KDIGO AKI guideline contains 87 individual

recommendations, of which 26 (30%) are ungraded,

39 (45%) are level 2 recommendations, and only 22

(25%) are level 1 recommendations, reflecting the

relative paucity of high-level data guiding the manage-

ment of AKI (Fig 1). In addition, many of the level 1

recommendations advise against the use of specific

agents or therapeutic interventions.

All members of the Work Group completed the

AGREE (Appraisal of Guideline for Research and

Evaluation) II instrument to assess the quality of theKDIGO AKI guideline.21-23 Mean Work Group scores

for each of the 23 elements and scaled domain scores

for the 6 domains are provided in Table 3, along with

the scoring range for domain and overall scores. The

domain scores ranged from 0.53 for applicability to

0.85 for editorial independence. The mean overall

score provided was 5.3 1.0 on a 7-point scale. All

Work Group members recommended the KDIGO

AKI guideline for use, although the majority sug-

gested that modifications could improve the guide-

line.

Figure 1. Strength of recommendation and level of evi-dence of the KDIGO Clinical Practice Guideline for Acute

Kidney Injury recommendations. Level 1 corresponds to arecommendation statement of “we recommend”; Level 2, to astatement of “we suggest”; Not Graded was used to provideguidance based on common sense or when the topic does notallow adequate application of evidence. The quality of support-ing evidence is graded from A t o D , with letter grades corre-sponding to high, moderate, low, and very low quality ofevidence, respectively.

Am J Kidney Dis. 2013;61(5):649-672 651

KDOQI Commentary


4/24

REVIEWOF KDIGOAKI RECOMMENDATIONS

DefinitionandClassificationofAKI

Commentary

Overview. The first group of recommendation state-ments in the KDIGO AKI Guideline addresses the

definition of AKI (Box 1). Of these 13 recommenda-tion statements, 12 are not graded. The KDIGO Work Group began by defining AKI by harmonizing theprior RIFLE and AKIN criteria.7,19 In the RIFLE

criteria (Table 1), AKI was defined based on a 50%increase in serum creatinine level occurring over 1-7days or the presence of oliguria for more than 6 hours.The AKIN criteria added an absolute increase inserum creatinine level of 0.3 mg/dL and reduced thetimeframe for the increase in serum creatinine level to

48 hours (Table 1). The KDIGO Work Group harmo-nized these 2 definitions, keeping the absolute in-crease in serum creatinine level of 0.3 mg/dL within48 hours from the AKIN definition, but returning to

Table 3. KDOQI Work Group’s Appraisal of the KDIGO AKI Guideline Using the AGREE II Instrument

Domain Element ScoreaScaled Domain

Scoreb

Scope and purpose 1. The overall objective(s) of the guideline is (are) specifically described. 6.0 0.9 0.83

2. The health question(s) covered by the guideline is (are) specifically

described.

6.1 0.8

3. The population (patients, public, etc) to whom the guideline is meant

to apply is specifically described.

5.8 1.3

Stakeholder involvement 4. The guideline development group includes individuals from all

relevant professional groups.

5.7 1.6 0.58

5. The views and preferences of the target population (patients, public,

etc) have been sought.

2.9 1.8

6. The target users of the guideline are clearly defined. 4.9 1.1

Rigor of development 7. Systematic methods were used to search for evidence. 6.0 1.0 0.76

8. The criteria for selecting the evidence are clearly described. 6.1 0.9

9. The strengths and limitations of the body of evidence are clearly

described.

6.1 0.9

10. The methods for formulating the recommendations are clearly

described.

5.9 0.9

11. The health benefits, side effects, and risks have been considered in

formulating the recommendations.

5.6 1.5

12. There is an explicit link between the recommendations and the

supporting evidence.

5.4 0.9

13. The guideline has been externally reviewed by experts prior to its

publication.

4.9 2.1

14. A procedure for updating the guideline is provided. 4.4 2.2

Clarity of presentation 15. The recommendations are specific and unambiguous. 4.9 0.9 0.73

16. The different options for management of the condition or health

issue are clearly presented.

5.1 1.5

17. Key recommendations are easily identifiable. 6.1 0.8

Applicability 18. The guideline describes facilitators and barriers to its application. 4.6 1.8 0.53

19. The guideline provides advice and/or tools on how therecommendations can be put into practice. 4.1

1.5

20. The potential resource implications of applying the

recommendations have been considered.

4.4 1.3

21. The guideline presents monitoring and/or auditing criteria. 3.7 1.9

Editorial independence 22. The views of the funding body have not influenced the content of the

guideline.

6.1 0.9 0.85

23. Competing interests of guideline development group members have

been recorded and addressed.

6.1 0.9

Abbreviation: AGREE, Appraisal of Guideline for Research and Evaluation.aGiven as mean standard deviation. Individual element statement is scored on a 7-point scale where 1 represents “strongly

disagree” and 7 represents “strongly agree.”bDomain scores are reported on a scale from 0-1, where a score of 0 would represent all reviewers providing the minimum possible

score for each element in the domain and a score of 1 indicating that allreviewers gave the highest possible score for allelements in the

domain.

Am J Kidney Dis. 2013;61(5):649-672652

Palevsky et al


5/24

the 7-day timeframe for the 50% increase in serumcreatinine level. With regard to pediatric AKI, theKDIGO definition did not adopt the smaller changesin estimated creatinine clearance proposed in thepRIFLE criteria. Rather, the KDIGO Work Groupsuggested that the absolute change in creatinine levelof 0.3 mg/dL that is part of the KDIGO AKIdefinition would capture most pediatric AKI. TheKDIGO definition considers a decrease in estimated

glomerular filtration rate (eGFR) to 35 mL/min/

1.73 m2 to be stage 3 AKI in pediatric patients, asinitially proposed in the pRIFLE criteria.20

Overall, while our KDOQI Work Group concurredwith the efforts on the part of KDIGO to meld the RIFLEand AKIN criteria into a uniform definition of AKI, wehave significant reservations regarding the applicabilityof this definition and staging system to clinical practice.The RIFLE and AKIN definitions and staging systems

have substantially enhanced the ability to conduct epide-miologic studies, and we support the use of the KDIGOAKI guideline definition and staging strategy for futureepidemiologic research until novel biomarkers facilitate

the development of better criteria. We concur that therigorous application of a standard definition will permitepidemiologic comparisons across populations and overtime. In addition, the definitions as described have valuein standardization of entry criteria and endpoints inclinical trials of AKI. However, we question whetherthese criteria are currently appropriate to guide clinicalmanagement of adult patients.

The successive stages of a serum creatinine–basedAKI definition reflect a tradeoff between sensitivity and

specificity. At low stages, sensitivity is high (ie, almostevery patient with true AKI is identified), but specificityis low (ie, many patients without true AKI are misidenti-fied as having AKI). As part of the decision to recom-mend a cutoff value based on a biomarker such as serumcreatinine or physiologic variable such as urine output,

the implications of the cutoff need to be carefully consid-ered. We thought that particularly in the United States,where defensive medicine is common due to the highlylitigious environment in which many physicians prac-tice, the KDIGO definition may result in a dramaticincrease in nephrology consultations and have the unin-

Box 1. Summary of KDIGO Recommendation Statements: Definition of AKI.

2.1.1: AKI is defined as any of the following ( Not Graded ):

● Increase in SCr by 0.3 mg/dL (26.5 mol/L) within 48 hours; or

● Increase in SCr to 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or

● Urine volume 0.5 mL/kg/h for 6 hours.

2.1.2: AKI is staged for severity according to the following criteria.a (Not Graded )Stage 1: Increase in SCr by 1.5-1.9 times baseline; OR

Increase in sSCr by 0.3 mg/dL (26.5 mol/L); OR

Urine output 0.5 mL/kg/h for 6-12 hours

Stage 2: Increase in SCr by 2.0-2.9 times baseline; OR

Urine output 0.5 mL/kg/h for 12 hours

Stage 3: Increase in SCr by 3.0 times baseline; OR

Increase in SCr to 4.0 mg/dL (353.6 mol/L); OR

Initiation of renal replacement therapy; OR

In patients18 years, decrease in eGFR to 35 mL/min/1.73 m2; OR

Urine output 0.3 mL/kg/h for 24 hours; OR

Anuria for 12 hours

2.1.3: The cause of AKI should be determined whenever possible. (Not Graded )

2.2.1: We recommend that patients be stratified for risk of AKI according to their susceptibilities and exposures. (1B )

2.2.2: Manage patients according to their susceptibilities and exposures to reduce the risk of AKI (see relevant guideline sections).

(Not Graded )

2.2.3: Test patients at increased risk for AKI with measurements of SCr and urine output to detect AKI. (Not Graded ) Individualize

frequency and duration of monitoring based on patient risk and clinical course. (Not Graded )

2.3.1: Evaluate patients with AKI promptly to determine the cause, with special attention to reversible causes. (Not Graded )

2.3.2: Monitor patients with AKI with measurements of SCr and urine output to stage the severity, according to Recommendation

2.1.2. (Not Graded )

2.3.3: Manage patients with AKI according to the stage (Fig 2) and cause. (Not Graded )

2.3.4: Evaluate patients 3 months after AKI for resolution, new onset, or worsening of pre-existing CKD. (Not Graded )

● If patients have CKD, manage these patients as detailed in the KDOQI CKD Guideline (Guidelines 7-15). (Not Graded )

● If patients do not have CKD, consider them to be at increased risk for CKD and care for them as detailed in the KDOQI CKD

Guideline 3 for patients at increased risk for CKD. (Not Graded )

Note: Conversion factor for SCr mg/dL to mol/L,88.4.

Abbreviations: AKI, acute kidney injury; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; SCr, serum

creatinine.

Reproduced with permission of KDIGO from the KDIGO Clinical Practice Guideline for Acute Kidney Injury .1aThe staging information is adapted from a table presented in the guideline.

Am J Kidney Dis. 2013;61(5):649-672 653

KDOQI Commentary


6/24

tended adverse consequence of diverting limited re-

sources toward a large number of patients for whom

specialty referral may have uncertain benefit.

However, we recognize that the clinical application

of the KDIGO AKI definition could increase the earlyrecognition of AKI. Given the current lack of effec-

tive pharmacologic interventions for AKI, early recog-nition based on small changes in serum creatinine

level or urine output could allow implementation of

simple interventions—such as avoiding potentially

nephrotoxic medications or diagnostic or therapeutic

procedures that are associated with increased risk of AKI unless clearly clinically indicated, or judicious

protocol-driven volume resuscitation—that could re-

duce the risk of more severe kidney injury.

In addition to these more global concerns, our Work Group identified several specific issues regarding the

definition and staging criteria that we believe require

specific comment, as discussed next. Inclusion of urine output into the definition of AKI.Both RIFLE and AKIN included duration of oliguria

in their definitions and staging criteria (Table 1).

Several criticisms have been offered of these urine

output criteria, many of which are acknowledged bythe KDIGO AKI Guideline Work Group but deserve

further mention. Only a small number of studies have

examined the urine output criteria for AKI and corre-

lated them with adverse clinical outcomes, in contrastto the numerous studies that have focused on the

serum creatinine criteria. The studies that have evalu-

ated the urine output component of the criteria have

found poor calibration between these criteria and theserum creatinine criteria.24 Specifically, when as-

sessed, there was poor prognostic correlation between

the briefer durations of oliguria and small changes in

serum creatinine level. Second, oliguria may be anappropriate response to volume depletion and hence

reflect under-resuscitation rather than injury to the

kidney, which is implicit in the term “AKI.” There-

fore, even demonstrating an association between oli-guria and adverse clinical outcomes is insufficient to

justify its incorporation into the definition of AKI.

Third, the use of a weight-based definition for AKI

limits its use in the obese due to the nonlinear relation-ship between body weight and urine output. Under the

current definition, urine output of 40 mL/h in a 90-kg

patient for 12 hours would lead to classification as

stage 2 AKI. Fourth, diuretic administration has beenshown to change RIFLE classification by urine output

criteria,24 as would be expected when a definition is

based on a physiologic variable that can be manipu-lated pharmacologically. Finally, the use of oliguria in

a definition of AKI may promote its use in clinical

practice as a surrogate end point. We know from

several studies that pharmacologic agents that can

increase urine output independent of augmentation of

kidney function, such as loop diuretics or dopamine,may not be helpful and may even be harmful in some

settings.25,26 While the inclusion of these criteria inthe AKI guideline may have the beneficial effect of

encouraging more rigorous documentation of urine

output and overall fluid balance in settings outside theoperating room and critical care units, there are also

risks of unintended consequences with defining tran-

sient oliguria as AKI. In particular, we believe that

current data are inadequate to support the reliance onoliguria as a surrogate end point in clinical trials or in

performance metrics. We note that pediatric, and in

particular neonatal, providers rely heavily on urine

output and weight-based fluid balance and thereforeinclusion of these parameters in the pediatric AKI

criteria is reasonable; furthermore, neonates in particu-

lar are unlikely to have morbid obesity and therefore

the methodological issues with weight-based urineoutput are somewhat less problematic. Nonetheless,

further research is needed in the pediatric population

to determine what metrics are best used to define AKI,

and practitioners should recognize that many of thesame limitations to the use of urine output criteria

apply in the pediatric population.

Use of small changes in serum creatinine to define AKI. The inclusion of a small absolute change inserum creatinine level in the AKIN definition of AKIwas based on the demonstration by Chertow et al4 that

minor fluctuations in serum creatinine concentration

were strongly associated with adverse outcomes in aretrospective analysis of data from individuals hospi-

talized at a single medical center. Although the asso-

ciation remained, albeit attenuated, after multivari-

able adjustment, only administrative data wereavailable for construction of the multivariable mod-

els, and residual confounding may have been present.

Small changes in serum creatinine level have also

been identified to be of prognostic importance insubsequent studies. Even a 0.1-mg/dL increase in

serum creatinine level appears to be associated with

increased risk compared to no change in serum creati-

nine level.27 Whether these small changes in serum

creatinine level reflect clinically meaningful fluctua-tions in kidney function that are causally linked to

adverse outcomes or are merely a marker of underly-ing vascular disease or diminished renal reserve, which

could be the actual mediators of the adverse out-

comes, remains unresolved. Furthermore, an implicit

assumption underlying the incorporation of smallchanges in serum creatinine concentration into the

definition of AKI is that GFR in an individual is

constant over time and not subject to physiologic

fluctuation. In addition, biological fluctuation in se-rum creatinine level may also result from variations in

Am J Kidney Dis. 2013;61(5):649-672654

Palevsky et al


7/24

diet, creatinine generation, tubular secretion, medica-

tions, and variability in sodium and volume homeosta-

sis that are within the physiologic range. Such fluctua-

tion in serum creatinine concentration is more

prominent in individuals with decreased renal reserveor overt CKD. For all these reasons, an absolute

change in serum creatinine level of 0.3 mg/dL mayrepresent a relatively inconsequential change in GFR

in patients with underlying CKD and not reflect super-

imposed acute pathology. Despite these concerns in

adult patients, in neonatal/pediatric patients, such small

changes in serum creatinine level may represent rela-tively large changes in actual GFR that should not be

disregarded. Whether novel biomarkers of tubular

injury may enhance risk stratification of patients with

small changes in serum creatinine level is a questionthat requires further investigation and may lead to

further refinement of AKI staging.

The independent role of duration of AKI. Severalrecent studies have suggested that duration of AKImay be a more important predictor of outcomes than

the magnitude of change in serum creatinine level.

For example, in one study, even a transient elevation

in creatinine level (3 days) was associated withincreased risk of death, and the risk of mortality was

greater in patients with prolonged duration of AKI.28

After adjustment for duration of AKI, staging was no

longer predictive of adverse outcomes. Unfortunately,

this important dimension can only be assessed retro-

spectively and cannot be included in prospectivestaging criteria; however, consideration should be

given to including an assessment of duration of AKI

in future criteria designed for epidemiologic studies.Pediatric-specific concerns. The KDOQI Work

Group also had several concerns regarding the appli-

cation the KDIGO definition and staging of AKI to the

pediatric population. One of the major concerns with

both the RIFLE and AKIN criteria is that they are

problematic for smaller (pediatric) patients with lowmuscle mass. The pRIFLE criteria were developed to

address the issues of applying the adult criteria to the

pediatric population.20 For example, because abnor-

mally elevated serum creatinine measurements are

often overlooked in pediatric patients (due to adultnormative data in laboratory readouts), utilization of the pRIFLE criteria might improve identification of

those with true AKI. The pRIFLE criteria have been

used widely in pediatric clinical research and efforts

are now being made to apply these criteria in clinical

practice. However, there are significant differencesbetween the KDIGO and pRIFLE criteria. Conse-

quently, further validation will be required prior to the

adoption of the KDIGO criteria into research and

practice. Specifically, pediatric nephrologists will wantto better understand whether the differences in the 2

definitions result in the identification of different

patient groups, and if so, what systematic biases may

be introduced by these differences. Thus, it was un-

clear to the KDOQI Work Group whether pediatric

nephrologists would widely embrace the new KDIGO

AKI definition or continue to apply the pRIFLE

criteria.In addition, most pediatric patients will not neces-

sarily have had previous serum creatinine measure-ments and therefore baseline renal function determina-

tion is often assumed to be normal, which may be

problematic. In addition, the neonatal population re-

mains an enigma in terms of renal function determina-tion, making both the definition and identification of

AKI in this population difficult. Many neonates have

not attained full renal mass development at birth and

are obligatorily born with low GFR, which improves

with growth and development. AKI in neonates is

often associated with high urine output, which may gounrecognized given the paucity of serum creatinine

measurements in this patient cohort. Finally, immedi-

ately after birth, serum creatinine level in neonatesoften reflects maternal creatinine levels, which must

be considered when evaluating renal function. How-

ever, the recommendation of a 0.3-mg/dL increase in

serum creatinine level (even in the context of baselinematernal creatinine level) should be sufficient to trig-

ger concern, and this component of the definition is

applicable in the neonatal population.

In addition to defining and staging AKI, the KDIGOguideline introduces the new term acute kidney dis-

ease (AKD), defined as AKI, or GFR 60 mL/min/

1.73 m2 for less than 3 months, or a decrease in GFR

by 35% or an increase in serum creatinine level by

50% for less than 3 months, or structural kidney

damage of less than 3 months’ duration. While weunderstand the nosological rationale for developing

terminology to describe patients with kidney disease

that does not meet the criteria for either AKI or CKD,

we have concern that the introduction of this terminol-ogy may confuse clinicians and inappropriately divert

attention away from diagnostic considerations. While

CKD encompasses a number of pathophysiologically

and histopathologically distinct diseases, arguably themajority of patients with CKD have diseases such as

hypertensive nephrosclerosis and diabetic nephroscle-

rosis, for which treatment approaches are similar.

However, in the acute setting, distinctions betweencauses of disease have greater consequence. To lump

the broad range of conditions that result in acute and

subacute kidney disease, ranging from acute tubular

necrosis to obstructive uropathy, atheroembolic dis-ease, and rapidly progressive glomerulonephritis, into

the single umbrella term of AKD runs the risk of

promoting diagnostic laziness among clinicians who

Am J Kidney Dis. 2013;61(5):649-672 655

KDOQI Commentary


8/24

would have a convenient name to apply rather than anabnormal laboratory value to investigate. We would

have welcomed a more in-depth discussion of whatspecific kidney diseases are likely to segregate toAKD as opposed to AKI or CKD and how the intro-

duction of a new term was thought by the authors tohelp in clinical practice. While AKD may be a usefulconstruct in epidemiologic studies, we believe the useof this term should be discouraged in clinical practice.

In contrast to our reservations regarding the intro-duction of the AKD terminology, we strongly concurwith the KDIGO recommendations that the cause of AKI should be determined whenever possible and that

patients with AKI should be evaluated promptly todetermine the cause, with special attention to revers-

ible causes. However, our Work Group had severalconcerns regarding several of the other recommenda-tions related to the evaluation and general manage-ment of patients with and at risk of AKI. Specifically,our Work Group has concerns regarding the recom-mendation to manage patients with AKI according tothe stage and cause. We believe that the stage-based

management recommendations (Fig 2) are not ad-equately evidence based. These recommendations im-plicitly assume homogeneity within each AKI stageand successive increases in severity across stages. Asa result of the lack of correlation between serum

creatinine level and GFR in the acute setting, a pa-tient’s serum creatinine level may increase, resulting

in apparent progression in AKI stage, despite improve-ment in GFR. Clearly no guideline can accommodateall the subtleties of clinical practice or substitute forclinical judgment, but the recommendations for man-agement overall were relatively nonspecific and un-likely to help in daily clinical practice. We are espe-cially concerned that the development of clinicalaction plans based onAKI stage may result in inappro-priate protocolization of care. While recommenda-

tions such as discontinuation of nephrotoxic agentswhen possible and ensuring volume status and perfu-sion pressure in high-risk patients or patients withAKI, waiting until stage 2 AKI to check for changes in

drug dosing implies that this need not be done earlier,while the recommendations for considering initiationof RRT and intensive care unit admission in stage 2AKI seem premature. Overall, we thought that the

extreme heterogeneity of AKI and its lack of consis-tent mapping to stages 1, 2, and 3 make the proposedstage-based management of AKI clinically unhelpfuland inapplicable to many patients.

We agree with the emphasis on close postdischargeclinical evaluation of patients with moderate to severeAKI given the recent identification of an associationbetween AKI and long-term outcomes such as renal

Figure 2. Stage-based management of acute kidney injury (AKI). Shading of boxes indicates priority of action—solid shading (withwhite lettering) indicates actions that are equally appropriate at all stages whereas graded shading (with black lettering) indicatesincreasing priority as intensity increases. Abbreviation: ICU, intensive care unit. Reproduced with permission of KDIGO from theKDIGO Clinical Practice Guideline for Acute Kidney Injury .1

Am J Kidney Dis. 2013;61(5):649-672656

Palevsky et al


9/24

function decline and mortality. However, we are con-cerned that clinicians may be overwhelmed by 3-monthfollow-up of many patients with stage 1 AKI, whowill constitute the majority of individuals identifiedby the AKI definition due to transient oliguria or smallchanges in serum creatinine level. The risk of progres-

sive CKD after AKI is related to the severity of AKI,16,29,30 suggesting that risk stratification on thebasis of AKI severity may be useful in guiding thetiming of outpatient follow-up. Those with stage 3AKI, for example, will likely require far earlier post-discharge follow-up. Furthermore, patients with AKIin the setting of pre-existing CKD or those whodevelop worsening CKD as a consequence of an

episode of AKI could represent a particularly high-risk group.

In the pediatric population, the 3-month time tofollow-up may be reasonable. The CKiD (ChronicKidney Disease in Children) national trial has identi-fied that a large number of the patients available forthat patient cohort were at-risk patients in the neonatalpopulation.31 Although the evidence for transitionfrom AKI to CKD in the pediatric population is alsoobservational and further epidemiologic research is

required, the number of pediatric patients with AKI ismuch smaller than in the adult population and thestakes of missing nascent CKD may be greater giventhe potential longer duration of follow-up than in theadult population. Thus, we would suggest that earlyfollow-up among pediatric patients with AKI is advis-able.

ImplicationsWithinUSHealthCare

1. The KDIGO definition and staging system forAKI provides an important tool for conducting epide-miologic studies and for the design of clinical trialsand helps increase awareness of the importance of small changes in kidney function in the acute setting.However, there is insufficient validation of this defini-tion and staging system for its use in the diagnosis andclinical management of patients. In particular, we donot believe that there are sufficient data to support use

of the stage-based management approach proposed in

the KDIGO guideline. Rather, management of pa-tients with AKI should be based on assessment of overall clinical status, including specific cause of AKI, trends in kidney function over time, comorbidconditions, assessment of volume status, and concomi-tant acid-base and electrolyte disturbances.

2. While AKI is an important risk factor for the

development and progression of CKD, the majority of patients with mild, readily reversible AKI (eg, thepatient with no baseline CKD who presents withreversible AKI in the setting of volume depletion) areat relatively low risk of progressive CKD. From a

public health standpoint in the United States, fol-low-up of kidney function after an episode of AKIshould be targeted to the highest risk populations,including neonatal/pediatric patients, individuals with

baseline CKD, and patients with severe AKI or whohave incomplete recovery of kidney function at hospi-

tal discharge.3. The KDIGO recommendations for definition and

staging of adult AKI should not be used for thedevelopment of clinical performance measures.

4. Administrative coding for AKI should not bebased solely on this definition and staging system.

PreventionandTreatmentofAKI

Commentary

The section of the KDIGO guideline on preventionand treatment of AKI includes 7 level 1 recommenda-tions and 22 level 2 recommendations (Box 2). Our

KDOQI Work Group agreed with the 7 level 1 recom-mendations and thought that they were generallyapplicable in the United States. These focused on theuse of vasopressors and fluids to treat patients inshock; avoidance of diuretics, dopamine, and recom-binant human IGF-1 (insulin-like growth factor 1) to

prevent or treat AKI; therapeutic drug monitoringduring the use of aminoglycosides; and avoidance of nephrotoxic medications when possible. Importantly,avoidance of nephrotoxins is not always possible. Forexample, some pathogens are not effectively treatedby azoles or echinocandins: Candida krusei is intrinsi-

cally resistant to azoles, and Candida parapsilosis isfrequently resistant to echinocandins.The KDOQI Work Group largely agreed with the

recommendation to use isotonic crystalloids ratherthan colloids for volume expansion in patients at risk of AKI or with AKI. In addition, we noted that t hereappears to be harm with starch-containing fluids.32-36

Therefore, these solutions should be avoided in pa-tients at risk of AKI or with AKI. Along the samelines, albumin resuscitation has been associated withharm in patients with traumatic brain injury andshould be avoided in that setting.37,38

There are also specific settings in which albumin is

appropriate for initial management of expansion of intravascular volume. Specifically, in patients withliver disease, intravenous albumin administration ap-pears to be beneficial for the prevention of renalfailure and death in patients with spontaneous bacte-rial peritonitis, as well as for the prevention of renalfailure in those undergoing large-volume paracente-sis.39,40 Along the same lines, the most recent diagnos-

tic criteria for hepatorenal syndrome include a lack of improvement in renal function after volume expan-sion with albumin (1 g/kg/d up to 100 g/d) for at least2 days and withdrawal of diuretic therapy.41 Data

Am J Kidney Dis. 2013;61(5):649-672 657

KDOQI Commentary


10/24

published since the KDIGOAKI guideline first appeared

suggest that there may be harm associated with theadministration of hyperchloremic intravenous solutions,including crystalloid42,43; however, these studies have

all been observational and this premise needs to be testedin a randomized clinical trial given the enormous effect

size observed and the inability to control for othertemporal trends in care in the prior studies.

With regard to the use of vasopressors in addition tointravenous fluids in patients with vasomotor shock,

we noted that fluid resuscitation is typically insuffi-cient to fully restore blood pressure to normal levels,which is critical for the prevention and management

of AKI. However, whether one vasopressor is moreeffective for patients with or at risk of AKI is un-known. In a large multicenter clinical trial of patients

with shock comparing dopamine and norepinephrinefor first-line vasopressor support, the use of dopamine

was associated with more adverse events in those withsepsis and with an increased risk of death in those with

cardiogenic shock.44 In a subsequent meta-analysis andsystematic review of patients with septic shock, dopa-

mine was associated with an increased risk of death andarrhythmias.45,46 Thus, we believe that dopamine should

be used with caution as the first-line agent of choice inpatients with shock at present.

Our Work Group did not fully agree with therecommendation to use protocol-based management

of hemodynamic and oxygenation parameters to pre-vent the development or worsening of AKI in high-risk patients in the perioperative setting or in patients

with septic shock. The group noted that the recommen-dation for early goal-directed therapy in patients withseptic shock is based primarily on single-center ran-

domized clinical trials47,48 and observational stud-ies.49-52 There was no assessment of renal outcomes

Box 2. Summary of KDIGO Recommendation Statements: Prevention and Treatment of AKI

3.1.1: In the absence of hemorrhagic shock, we suggest using isotonic crystalloids rather than colloids (albumin or starches) as initial

management for expansion of intravascular volume in patients at risk for AKI or with AKI. (2B )

3.1.2: We recommend the use of vasopressorsin conjunction with fluids in patients with vasomotor shock with, or at risk for, AKI. (1C )

3.1.3: We suggest using protocol-based management of hemodynamic and oxygenation parameters to prevent development or

worsening of AKI in high-risk patients in the perioperative setting (2C ) or in patients with septic shock (2C ).

3.3.1: In critically ill patients, we suggest insulin therapy targeting plasma glucose 110-149 mg/dL (6.1-8.3 mmol/L). (2C )3.3.2: We suggest achieving a total energy intake of 20-30 kcal/kg/d in patients with any stage of AKI. (2C )

3.3.3: We suggest to avoid restriction of protein intake with the aim of preventing or delaying initiation of RRT. (2D )

3.3.4: We suggest administering 0.8-1.0 g/kg/d of protein in noncatabolic AKI patients without need for dialysis (2D ), 1.0-1.5 g/kg/d in

patients with AKI on RRT (2D ), and up to a maximum of 1.7 g/kg/d in patients on continuous renal replacement therapy (CRRT)

and in hypercatabolic patients. (2D )

3.3.5: We suggest providing nutrition preferentially via the enteral route in patients with AKI. (2C )

3.4.1: We recommend not using diuretics to prevent AKI. (1B )

3.4.2: We suggest not using diuretics to treat AKI, except in the management of volume overload. (2C )

3.5.1: We recommend not using low-dose dopamine to prevent or treat AKI. (1A)

3.5.2: We suggest not using fenoldopam to prevent or treat AKI. (2C )

3.5.3: We suggest not using atrial natriuretic peptide (ANP) to prevent (2C ) or treat (2B ) AKI.

3.6.1: We recommend not using recombinant human (rh)IGF-1 to prevent or treat AKI. (1B )

3.7.1: We suggest that a single dose of theophylline may be given in neonates with severe perinatal asphyxia, who are at high risk of

AKI. (2B )

3.8.1: We suggest not using aminoglycosides for the treatment of infections unless no suitable, less nephrotoxic, therapeuticalternatives are available. (2A)

3.8.2: We suggest that, in patients with normal kidney function in steady state, aminoglycosides are administered as a single dose

daily rather than multiple-dose daily treatment regimens. (2B )

3.8.3: We recommend monitoring aminoglycoside drug levels when treatment with multiple daily dosing is used for more than 24

hours. (1A)

3.8.4: We suggest monitoring aminoglycoside drug levels when treatment with single-daily dosing is used for more than 48 hours.

(2C )

3.8.5: We suggest using topical or local applications of aminoglycosides (e.g., respiratory aerosols, instilled antibiotic beads), rather

than i.v. application, when feasible and suitable. (2B )

3.8.6: We suggest using lipid formulations of amphotericin B rather than conventional formulations of amphotericin B. (2A)

3.8.7: In the treatment of systemic mycoses or parasitic infections, we recommend using azole antifungal agents and/or the

echinocandins rather than conventional amphotericin B, if equal therapeutic efficacy can be assumed. (1A)

3.9.1: We suggest that off-pump coronary arterybypass graft surgery not be selected solely for the purpose of reducing perioperative

AKI or need for RRT. (2C)

3.9.2: We suggest not using NAC to prevent AKI in critically ill patients with hypotension. (2D) 3.9.3: We recommend not using oral or i.v. NAC for prevention of postsurgical AKI. (1A)

Abbreviations: AKI, acute kidney injury; IGF-1, insulin-like growth factor 1; i.v., intravenous; NAC, N -acetylcysteine; RRT, renal

replacement therapy.

Reproduced with permission of KDIGO from the KDIGO Clinical Practice Guideline for Acute Kidney Injury .1

Am J Kidney Dis. 2013;61(5):649-672658

Palevsky et al


11/24

in the original randomized clinical trial, so it is un-

clear if the intervention had any impact on renal

outcomes. Similarly, perioperative protocols have simi-

larly shown aggregate improvement when assessed in

a meta-analysis, but individual studies have beenlimited by small numbers and single-center design.53

Furthermore, our Work Group thought that the proto-col must be specified. That is, any protocol that is

instituted based on this recommendation should be

one that has been previously studied and validated.

For example, previous studies of increasing oxygentransport have demonstrated that the use of dobut-

amine to increase oxygen transport can worsen mortal-

ity,54 although the Rivers et al47 study of early goal-

directed therapy suggests that dobutamine in an

appropriate clinical context may not be harmful andmay have benefit. Thus, medical centers adopting

protocolized care should only adopt protocols that

have been previously shown to be helpful and demon-strated no harm. If de novo protocols are developedfor use, they should be used in the confines of a

clinical trial to ensure no harm.

With regard to glycemic control, we agreed with

the recommended target of 110-149 mg/dL, but notedthat emerging evidence suggests that rapid and sus-

tained correction of glycemia in diabetic patients with

previous poor glycemic control may have worse out-

comes.55 Our Work Group agreed with the recommen-

dations for nutritional support in AKI, but noted that

the evidence base for these recommendations is lim-

ited. Specifically, the guideline recommends total en-ergy intake of 20-30 kcal/kg/d in patients with any

stage of AKI with administration of 0.8-1.0 g/kg/d of

protein in noncatabolic patients with AKI without

need for dialysis, 1.0-1.5 g/kg/d in patients with AKIon RRT, and up to a maximum of 1.7 g/kg/d in

patients on continuous RRT (CRRT) and in hypercata-

bolic patients. The provision of protein to patients

with AKI is intended to avoid marked net negativenitrogen balance. Patients with AKI on RRT will have

additional protein loss as amino acids are removed.

Therefore, these patients require additional protein

compared with patients with AKI who are not on RRT.

Similarly, patients who are hypercatabolic will re-quire additional protein to avoid net negative nitrogen

balance. Along the same lines, the KDOQI Work

Group agreed with the recommendation to avoidrestriction of protein intake with the aim of preventing

or delaying initiation of RRT. We also agreed with the

recommendation to provide nutrition preferentially by

the enteral route in patients with AKI. The Work Group noted that although evidence is more limited in

the setting of AKI,56 in a recent large randomized

clinical trial of critically ill patients, early parenteral

nutrition was associated with a higher rate of compli-

cations, primarily infectious complications.57 Along

the same lines, recent trials suggest that enteral feed-

ing is tolerated by either the nasogastric or nasojejunal

routes.58,59

Nutritional support in pediatric patients must in-

clude the recognition that these patients are generally

in a developmental growth phase; thus, their require-ments may be increased compared with adult patients.

Recent estimates have been published in terms of

estimated protein/amino acid supplementation in criti-

cally ill children and suggest that protein require-ments are on the order of 2-3 g/kg/d for children aged

0-2 years, 1.5-2.0 g/kg/d for children aged 2-13 years,

and 1.5 g/kg/d for adolescents aged 13-18 years.60

Children requiring RRT appear to need supplementa-

tion beyond this.61

There are no pharmacotherapies available for the

prevention or treatment ofAKI in adults, so recommen-

dations to avoid these are reasonable. Specifically, weagreed that although there is theoretical benefit to theuse of loop diuretics to prevent AKI, there are no data

to support the use of diuretics to prevent AKI. Recent

studies in patients undergoing cardiac surgery or con-

trast studies suggest that the use of diuretics does notprevent AKI62 and, in the case of contrast administra-

tion, increases the risk of AKI.63,64 The KDOQI Work Group thought that it was important to comment on

the use of diuretics in patients with AKI and rhabdo-

myolysis. With regard to osmotic diuretics, one retro-

spective study has suggested that the use of mannitoladministration may be of benefit only in patients with

marked elevations in creatinine kinase level (30,000

U/L).65 However, even in these patients with severe

rhabdomyolysis, the true benefit associated with man-

nitol administration remains undefined. Furthermore,

mannitol should be administered carefully and iscontraindicated in patients with oligoanuria. Diuretics

may be used for the treatment of volume overload in

AKI.66 We agree that low-dose dopamine, fenoldo-

pam, IGF-1, and N -acetylcysteine (NAC) should notbe used for the treatment or prevention of AKI.

We concur with the recommendation to administer

a single dose of theophylline to neonates with severe

perinatal asphyxia who are at high risk of AKI.Several clinical trials in the neonatal population sug-gest that although mortality outcomes are not af-

fected, improved fluid control and higher GFR are

associated with theophylline administration in this

setting.67-69 A similar renal-selective response has

been demonstrated in asphyxiated term newborns

receiving a single theophylline dose in the first 60minutes of life.70 Given the generally physiologic

hyperactive state of the renal autoregulatory system

apparent at transition from in utero to ex utero environ-

ments and the role that adenosine plays in these

Am J Kidney Dis. 2013;61(5):649-672 659

KDOQI Commentary


12/24

processes, the use of theophylline in the aforemen-tioned settings is reasonable.

A substantial number of recommendations weremade with regard to the use of aminoglycosides and

antifungal agents. Our Work Group agreed with theserecommendations but noted that there are situations in

which aminoglycosides or multidose regimens arepreferable (eg, multiple dose regimens remain thestandard of care for enterococcal endocarditis). Wealso noted that while local instillation of aminoglyco-

sides is reasonable, it is unknown what the incidenceof nephrotoxicity is with local administration of ami-

noglycosides; for example, there are case reports of nephrotoxicity associated with inhaled tobramycin

therapy.71-73

With regard to the use of lipid formulations of

amphotericin B rather than conventional formulationsof amphotericin B, we note that it has been suggested

that the decreased incidence of AKI and the associateddecrease in hospitalization costs makes the lipid for-

mulations cost-effective compared to conventionalformulations of amphotericin B.74,75 Furthermore,

other simple strategies that may reduce the risk of nephrotoxicity include discontinuation of diuretics,sodium loading and volume repletion, and potassium

and magnesium supplementation, particularly whenusing non-liposomal preparations of amphotericin B.76

The 2 most significant risk factors for the develop-ment of AKI following cardiac surgery are cardiopul-

monary bypass time and a history of CKD.77,78 As aresult, there has been considerable interest in the

potential for off-pump bypass to decrease the risk of AKI. The largest retrospective study focused on pa-

tients with CKD was published after the KDIGO AKIguideline.79 This study examined nonemergent iso-

lated coronary artery bypass grafting (CABG) casesin the Society of Thoracic Surgery Database from2004 through 2009 (N 742,909). Among patients

with eGFR of 15-29 mL/min/1.73 m2, off-pumpCABG was associated with a decreased risk of postop-

erative RRT (risk difference, 2.79; 95% confidenceinterval, 1.37-4.20) in the propensity-adjusted analy-

sis (P 0.01). There was no difference in those with

less advanced CKD, although those with eGFR of 30-59 mL/min/1.73 m2 were examined in aggregaterather than as separately as CKD stages 3a and 3b.

This potential benefit needs to be balanced against theconcern of higher graft occlusion rates using off-pump techniques.80,81


1. In the United States, starch-containing intrave-

nous fluids should be avoided. The use of albumin forresuscitation should be limited to specific situations in

which it is clear that albumin is of benefit, given the

increased costs of these solutions compared to crystal-

loid and the intermittent nationwide shortages of these

solutions. Recent studies have suggested that there

may be harm with hyperchloremic intravenous solu-tions (eg, isotonic saline), but this needs to be further

tested prior to the widespread use of balanced electro-

lyte solutions with lower chloride content (eg, Plasma-Lyte, Hartmann’s and lactated Ringer’s) in the United

States.

2. With regard to vasopressor support in patients

with shock, dopamine is associated with an increasedrate of complications in patients with septic and

cardiogenic shock compared to norepinephrine. Al-

though this needs to be further tested and a number of

guidelines still recommend the use of dopamine as afirst-line agent, norepinephrine should be used as a

first-line agent over dopamine unless there are spe-

cific contraindications to the use of norepinephrine.

3. Protocol-based management of perioperative pa-tients and patients with sepsis is a reasonable ap-proach, but the protocols for such management need

to be further developed and tested. We note that

several large randomized clinical trials will test proto-

col-based management of sepsis (ClinicalTrials.govidenti-fiers NCT00975793 and NCT00510835 and Interna-

tional Standard Randomised Controlled Trial Number

ISRCTN36307479). Until then, care should not be

benchmarked based on the implementation of suchprotocols within a given time frame; it is reasonable to

use time to antibiotics and time to fluid administration

as benchmarks for care in sepsis.

4. A target blood glucose level of 110-149 mg/dL incritically ill patients may be associated with decreased

risk of AKI and other morbidity and mortality. How-

ever, emerging evidence suggests that rapid and sus-

tained correction of hyperglycemia in diabetic pa-tients with previous poor glycemic control may have

worse outcomes.

5. Nutritional support in patients with AKI should

be provided by the enteral route when possible. Pro-tein supplementation should not be withheld to delay

the initiation of RRT. Patients with AKI are often

highly catabolic and protein requirements typically

increase with RRT due to amino acid loss, so nutri-tional prescriptions for patients with AKI need toreflect these considerations.

6. No agents are recommended for the treatment or

prevention of AKI in adults; a single dose of theophyl-

line can be provided to neonates at risk of AKI.7. The cost-effectiveness of the widespread use of

liposomal amphotericin B should be studied. Therapeu-

tic drug monitoring for aminoglycosides should re-

main standard of care.8. Off-pump CABG may be of benefit to reduce the

risk of RRT in those with advanced CKD, but further

Am J Kidney Dis. 2013;61(5):649-672660

Palevsky et al

http://www.clinicaltrials.gov/http://www.clinicaltrials.gov/


13/24

studies are warranted. Off-pump CABG should not beconsidered standard of care in those with CKD.

Contrast-InducedAKI

Commentary

The KDIGO guideline contains 12 recommenda-tions on prevention of contrast-induced AKI; 5 are notgraded, 4 are level 1 recommendations, and the remain-ing 3 are level 2 recommendations (Box 3). The firstof these recommendations is that contrast-induced

AKI be defined and staged using the KDIGO defini-tion and staging criteria. This recommendation makessense from the standpoint of consistency and is gener-

ally applicable in the United States, albeit with thelimitations noted in the previous comments on defini-tion and staging. However, we note that most clinicalstudies related to contrast-induced AKI have usedalternative definitions based on increments in serumcreatinine level of 25% or 50% relative to base-line and/or an absolute change in serum creatininelevel 0.5 mg/dL within 2-5 days following the

administration of iodinated contrast media. Althougha multitude of largely observational studies have dem-

onstrated associations of contrast-induced AKI, de-fined by these changes in serum creatinine level, withserious adverse events, the causal nature of suchassociations remains unproved, leaving unansweredthe question of how to best define “clinically signifi-cant” contrast-induced AKI. Thus, the recommenda-

tion to operationalize the definition of contrast-inducedAKI within the KDIGO framework is justified.Furthermore, applicability of the urine output criteriato the diagnosis and staging for this form of AKI isuncertain. Most episodes of contrast-induced AKI arenonoliguric. In addition, most contrast-enhanced radio-

graphic procedures are performed in the outpatientsetting, where monitoring of urine volume is not

performed and is impractical. Furthermore, recogniz-

ing that the majority of clinicians performing contrast-

enhanced procedures are not nephrologists, it is impor-tant that future efforts to refine the definition of

contrast-induced AKI include input from national and

international radiology and cardiology societies.

Underlying impairment in renal function is theprincipal risk factor for contrast-induced AKI. There-

fore, identification of patients with decreased kidney

function is essential in order to optimize the benefit of

preventive care. However, measuring serum creati-nine prior to all contrast-enhanced procedures is nei-

ther practical nor feasible. Simple questionnaires have

been shown to be effective for the identification of

patients at higher risk of abnormal underlying renal

function.82 In patients without a recent serum creati-

nine measurement, it is reasonable in the UnitedStates to use such questionnaires to identify patients

who should have serum creatinine measured prior to

contrast administration. The use of dipstick testing of

urine for protein is also suggested as a means of

identifying pre-existing kidney disease. Our Work Group had reservations regarding this approach and

suggests that further validation of this approach is

needed before widespread adoption of this strategy isconsidered. Additional risk factors for contrast-

induced AKI, including diabetes in the setting of renal

impairment, heart failure, repeated contrast exposureover short periods, and concomitant nephrotoxin ad-

ministration (eg, nonsteroidal anti-inflammatory drugs

and aminoglycosides) are important to recognize.

Equipoise on the impact of discontinuing angiotensin-converting enzyme–inhibitor and angiotensin recep-

Box 3. Summary of KDIGO Recommendation Statements: Contrast-Induced AKI

4.1: Define and stage AKI after administration of intravascular contrast media as per Recommendations 2.1.1-2.1.2. (Not Graded )

4.1.1: In individuals who develop changes in kidney function after administration of intravascular contrast media, evaluate for CI-AKI

as well as for other possible causes of AKI. ( Not Graded )

4.2.1: Assess the risk for CI-AKI and, in particular, screen for pre-existing impairment of kidney function in all patients who are

considered for a procedure that requires intravascular (i.v. or i.a.) administration of iodinated contrast medium. (Not Graded )

4.2.2: Consider alternative imaging methods in patients at increased risk for CI-AKI. (Not Graded )4.3.1: Use the lowest possible dose of contrast medium in patients at risk for CI-AKI. (Not Graded )

4.3.2: We recommend using either iso-osmolar or low-osmolar iodinated contrast media, rather than high-osmolar iodinated contrast

media in patients at increased risk of CI-AKI. (1B )

4.4.1: We recommend i.v. volume expansion with either isotonic sodium chloride or sodium bicarbonate solutions, rather than no i.v.

volume expansion, in patients at increased risk for CI-AKI. (1A)

4.4.2: We recommend not using oral fluids alone in patients at increased risk of CI-AKI. (1C )

4.4.3: We suggest using oral NAC, together with i.v. isotonic crystalloids, in patients at increased risk of CI-AKI. (2D )

4.4.4: We suggest not using theophylline to prevent CI-AKI. (2C )

4.4.5: We recommend not using fenoldopam to prevent CI-AKI. (1B )

4.5.1: We suggest not using prophylactic intermittent hemodialysis (IHD) or hemofiltration (HF) for contrast-media removal in patients

at increased risk for CI-AKI. (2C )

Abbreviations: AKI, acute kidney injury; CI-AKI, contrast-induced acute kidney injury; i.a., intra-arterial; i.v., intravenous; NAC,

N -acetylcysteine.

Reproduced with permission of KDIGO from the KDIGO Clinical Practice Guideline for Acute Kidney Injury .

1

Am J Kidney Dis. 2013;61(5):649-672 661

KDOQI Commentary


14/24

tor blocker therapy prior to contrast administration

persists and the KDIGO AKI guideline acknowledges

the inadequacy of the evidence to support the discon-

tinuation of these agents prior to contrast-enhanced

procedures. While the administration of loop diureticsfor the purpose of preventing contrast-induced AKI is

ineffective and potentially harmful, there are no datato support the recommendation to routinely discon-

tinue these agents in all patients prior to contrast

administration.

In patients at increased risk of contrast-induced

AKI, it is appropriate to discuss the risk to benefitratio of the planned procedure with the practitioner

performing the study (ie, radiologist or interventional-

ist), as well as with the patient. In considering alterna-

tive procedures that do not involve the administrationof iodinated contrast, the risk of nephrogenic systemic

fibrosis associated with the administration of gadolin-

ium-based contrast agents is important given the po-tential morbidity associated with this condition. Pa-tients with eGFR 30 mL/min/1.73 m2 and patientswith AKI are at risk of nephrogenic systemic fibrosis

and appropriate cautionary measures should be taken

regarding gadolinium-based contrast agents in this

group. While the KDOQI Work Group agrees with theimportance of avoiding unnecessary radiocontrast ad-

ministration in high-risk patients, a cautionary note is

required because several studies have suggested that

concern over contrast-induced AKI leads to underuti-lization of imaging techniques, particularly coronary

angiography, in high-risk patients with CKD.83

Studies of the association of dose of contrast me-

dium, considered as overall volume and grams of

iodine per eGFR ratio, with risk of contrast-induced

AKI suggest that higher doses are associated withgreater risk.84-86 Recommendations to consider notonly the total volume of contrast, but also the grams of

iodine per eGFR ratio, are reasonable based on avail-

able evidence, yet are most likely to be applicable to

radiologists and interventionalists performing contrast-enhanced procedures. Furthermore, routine calcula-

tion of the grams of iodine per eGFR ratio adds a layer

of complexity to the conduct of contrast-enhanced

procedures that may not be readily acceptable to allclinicians.

The specific contrast agent used also has an effect

on the risk of contrast-induced AKI. High-osmolal

contrast media are associated with higher rates of

contrast-induced AKI compared with low-osmolalagents in at-risk patients and should not be used in this

patient group.87 Clinical trials and meta-analyses com-paring the nephrotoxicity of low-osmolal contrast

agents with iso-osmolal contrast have yielded conflict-

ing results.88,89 Guidelines issued by the American

Heart Association/American College of Cardiology in

2009 recommended the use of iso-osmolal or low-

osmolal contrast exclusive of iohexol and ioxaglate in

patients with non–dialysis-dependent CKD undergo-

ing angiography based on data demonstrating higherrates of contrast-induced AKI among patients who

received these 2 agents compared with iso-osmolal

contrast and other low-osmolal agents.90

The recom-mendation of our Work Group is to follow the guide-

lines outlined by the American Heart Association/

American College of Cardiology in 2009. It is

important to note that iodixanol (Visipaque) is theonly iso-osmolal contrast agent clinically available in

the United States; there is a substantially higher cost

for brand-name Visipaque than the low-osmolal con-

trast agents, which may be important to consider indecisions related to choice of contrast.

The provision of intravenous fluids prior to and

after the administration of iodinated contrast media is

the primary intervention with demonstrated effective-ness for the prevention of contrast-induced AKI in

high-risk patients. We concur with the recommenda-

tion to not use oral fluids alone in patients at increased

risk of contrast-induced AKI. Controversy exists re-garding the benefit of isotonic sodium bicarbonate

administration compared to isotonic saline solution,

with divergent results reported from the multiple

small- to medium-sized clinical trials91-99 and meta-

analyses.100-110 Given the divergent results of studies

to date and the recognition that none of the random-

ized clinical trials to date have demonstrated that

isotonic bicarbonate is less effective than isotonicsaline solution, the KDIGO guideline recommenda-

tion to use either isotonic fluid in high-risk patients is

appropriate. The guideline makes an important men-

tion of the potential for compounding errors withsodium bicarbonate administration because no com-

mercially available isotonic bicarbonate solutions are

available, and the attendant risk for the administration

of hypertonic solutions. This risk is not associatedwith the provision of premixed saline solution. It is

also important to note that the additional time needed

to prepare isotonic sodium bicarbonate solution is not

required when administering standard saline solu-

tions. Therefore, the administration of isotonic salinesolution may be preferable in situations in which

emergent contrast procedures are indicated.

Acute administration of both mannitol and furo-semide has been associated with increased risk of

contrast-induced AKI.63,64 However, a series of recent

trials examined the benefit of generating high urine

flow rates using furosemide and saline solution infu-sions combined with a device that matches intrave-

nous fluid administration with urine output.111,112

These trials, which randomly assigned patients to this

strategy or to conventional periprocedural intrave-

Am J Kidney Dis. 2013;61(5):649-672662

Palevsky et al


15/24

nous fluids, reported lower rates of contrast-induced

AKI among patients randomly assigned to this device.

However, these studies were relatively small and did

not confirm whether sodium intake in the form of

intravenous fluids was matched to urinary sodiumexcretion in patients randomly assigned to the device.

Recognizing that urine composition following furo-semide administration is likely to be hypotonic rela-

tive to saline, patients randomly assigned to the device-

based protocol may have experienced net positive

sodium balance, which could confound the interpreta-

tion of the benefits of this device.A multitude of clinical trials have investigated

NAC for the prevention of contrast-induced AKI and

generated, much like the studies comparing isotonic

bicarbonate with isotonic saline solution, highly con-flicting findings.113-138 These studies have been lim-

ited by small study populations, clinically implausible

effect sizes, and a paucity of data for the effect of NAC on “hard” patient outcomes. Meta-analyses basedon these trials also documented conflicting findings

on the efficacy of NAC and underscore the limitations

in the primary clinical trials.139-142 In 2011, a large

randomized controlled trial of 2,308 patients reported

no reduction in the rate of contrast-induced AKI with1,200 mg of oral NAC dosed daily for 2 days as

compared to placebo.143 While this study is larger

than all prior published trials of NAC, several limita-

tions to its design have been raised, including the fact

that only 15.7% of study participants had a serumcreatinine level 1.5 mg/dL and the baseline serum

creatinine level may have been obtained up to 90 days

prior to the angiographic procedure. Intravenous NAC

is associated with potentially serious adverse effects

and, in the absence of sound data supporting itseffectiveness, should not be routinely administered

for the prevention of contrast-induced AKI. However,

oral NAC is inexpensive and largely devoid of ad-

verse side effects in the doses employed to preventcontrast-induced AKI. Therefore, the recommenda-

tion to administer oral NAC together with intravenous

isotonic crystalloid is not inappropriate despite the

questions of its efficacy. However, oral NAC should

not be used in lieu of intravenous isotonic crystalloidin high-risk patients. While the KDIGO guideline

does not recommend a specific dose or duration of

therapy, data suggesting a possible dose-dependenteffect justify the administration of 1,200 mg by mouth

twice daily for 2 days.

Our Work Group concurred with the KDIGO recom-

mendations against the use of fenoldopam and theoph-ylline for prevention of contrast-induced AKI. Al-

though preliminary uncontrolled trials of fenoldopam

suggested a benefit with regard to prevention of con-

trast-inducedAKI, this was not confirmed in a random-

ized controlled trial.144 While studies have suggested

a potential benefit to the adenosine antagonist theoph-

ylline for the prevention of contrast-induced AKI, the

data to date are not conclusive.145 Moreover, unlike

NAC, theophylline is associated with potential cardio-

vascular side effects and has numerous drug interac-

tions. Our KDOQI Work Group also concurred withthe recommendations not to use prophylactic hemodi-

alysis or hemofiltration for contrast media removal

and prevention of contrast-induced AKI. Although

extracorporeal therapies are able to remove contrast

media from the circulation, the rate of removal is

unlikely to prevent the kidney damage, which devel-

ops within minutes of contrast administration. Meta-

analysis of clinical trials of hemodialysis and hemofil-

tration have demonstrated an absence of benefit and

potential risk of harm with prophylactic hemodialy-

sis.146


1. All patients undergoing contrast-enhanced imag-

ing procedures should be evaluated for risk of AKI.

Screening can most appropriately be performed using

standardized questionnaires. Routine measurement of

serum creatinine in patients identified as low risk by

questionnaire is not indicated; however, if there is any

question regarding risk of kidney disease, serum creat-

inine level should be obtained prior to contrast admin-

istration.

2. The risks and benefits of contrast administration

need to be carefully evaluated in patients at high risk of contrast-induced AKI. The risk of contrast-induced

AKI should not preclude the performance of needed

diagnostic imaging and therapeutic procedures in high-

risk patients.

3. Iso-osmolal or selected low-osmolal contrast in

the lowest possible dose should be used in high-risk

patients.

4. The only intervention that has consistently been

demonstrated to decrease the risk of contrast-induced

AKI is periprocedural intravenous volume administra-

tion using isotonic crystalloid. Thus, all patients at

increased risk of contrast-induced AKI should receiveperiprocedural intravenous isotonic crystalloid. The

optimal rate of fluid administration remains uncertain,

and whether bicarbonate administration is associated

with greater benefit at risk reduction than saline re-

mains unresolved.

5. The benefit associated with NAC administration

remains uncertain. Given the minimal risk and cost

associated with this agent, we do not recommend

against its use, although it should not be used in lieu

of more effective interventions, particularly periproce-

dural administration of isotonic crystalloid.

Am J Kidney Dis. 2013;61(5):649-672 663

KDOQI Commentary


16/24

Box 4. Summary of KDIGO Recommendation Statements: Dialysis Interventions for Treatment of AKI

5.1.1: Initiate RRT emergently when life-threatening changes in fluid, electrolyte, and acid-base balance exist. (Not Graded )

5.1.2: Consider the broader clinical context, the presence of conditions that can be modified with RRT, and trends of laboratory

tests—rather than single BUN and creatinine thresholds alone—when making the decision to start RRT. (Not Graded )

5.2.1: Discontinue RRT when it is no longer required, either because intrinsic kidney function has recovered to the point that it is

adequate to meet patient needs, or because RRT is no longer consistent with the goals of care. ( Not Graded )

5.2.2: We suggest not using diuretics to enhance kidney function recovery, or to reduce the duration or frequency of RRT. (2B )5.3.1: In a patient with AKI requiring RRT, base the decision to use anticoagulation for RRT on assessment of the patient’s potential

risks and benefits from anticoagulation (see Figure 17). (Not Graded )

5.3.1.1: We recommend using anticoagulation during RRT in AKI if a patient does not have an increased bleeding risk or

impaired coagulation and is not already receiving systemic anticoagulation. (1B)

5.3.2: For patients without an increased bleeding risk or impaired coagulation and not already receiving effective systemic

anticoagulation, we suggest the following:

5.3.2.1: For anticoagulation in intermittent RRT, we recommend using either unfractionated or low-molecular-weight heparin,

rather than other anticoagulants. (1C)

5.3.2.2: Foranticoagulation in CRRT, we suggest using regional citrate anticoagulationrather than heparin in patients who do

not have contraindications for citrate. (2B)

5.3.2.3: For anticoagulation during CRRT in patients who have contraindications for citrate, we suggest using either

unfractionated or low-molecular-weight heparin, rather than other anticoagulants. (2C)

5.3.3: For patients with increased bleeding risk who are not receiving anticoagulation, we suggest the following for anticoagulation

during RRT:

5.3.3.1: We suggest using regional citrate anticoagulation, rather than no anticoagulation, during CRRT in a patient withoutcontraindications for citrate. (2C)

5.3.3.2: We suggest avoiding regional heparinization during CRRT in a patient with increased risk of bleeding. (2C)

5.3.4: In a patient with heparin-induced thrombocytopenia (HIT), all heparin must be stopped and we recommend using direct

thrombin inhibitors (such as argatroban) or Factor Xa inhibitors (such as danaparoid or fondaparinux) rather than other or no

anticoagulation during RRT. (1A)

5.3.4.1: In a patient with HIT who does not have severe liver failure, we suggest using argatroban rather than other thrombin

or Factor Xa inhibitors during RRT. (2C )

5.4.1: We suggest initiating RRT in patientswith AKI viaan uncuffednontunneleddialysis catheter, rather thana tunneledcatheter. (2D)

5.4.2: When choosing a vein for insertion of a dialysis catheter in patients with AKI, consider these preferences (Not Graded ):

● First choice: right jugular vein;

● Second choice: femoral vein;

● Third choice: left jugular vein;

● Last choice: subclavian vein with preference for the dominant side.

5.4.3: We recommend using ultrasound guidance for dialysis catheter insertion. (1A)

5.4.4: We recommend obtaining a chest radiograph promptly after placement and before first use of an internal jugular or subclaviandialysis catheter. (1B)

5.4.5: We suggest not using topical antibiotics over the skin insertion site of a nontunneled dialysis catheter in ICU patients with AKI

requiring RRT. (2C)

5.4.6: We suggest not using antibiotic locks for prevention of catheter-related infections of nontunneled dialysis catheters in AKI

requiring RRT. (2C)

5.5.1: We suggest to use dialyzers with a biocompatible membrane for IHD and CRRT in patients with AKI. (2C)

5.6.1: Use continuous and intermittent RRT as complementary therapies in AKI patients. (Not Graded)

5.6.2: We suggest using CRRT, rather than standard intermittent RRT, for hemodynamically unstable patients. (2B)

5.6.3: We suggest using CRRT, rather than intermittent RRT, for AKI patients with acute brain injury or other causes of increased

intracranial pressure or generalized brain edema. (2B )

5.7.1: We suggest using bicarbonate, rather than lactate, as a buffer in dialysate and replacement fluid forRRT in patients with AKI. (2C)

5.7.2: We recommend using bicarbonate, rather than lactate, as a buffer in dialysate and replacement fluid for RRT in patients with

AKI and circulatory shock. (1B)

5.7.3: We suggest using bicarbonate, rather than lactate, as a buffer in dialysate and replacement fluid for RRT in patients with AKI

and liver failure and/or lactic acidemia. (2B)

5.7.4: We recommend that dialysis fluids and replacement fluids in patients with AKI, at a minimum, comply with American

Association of Medical Instrumentation (AAMI) standards regarding contamination with bacteria and endotoxins. (1B)

5.8.1: The dose of RRT to be delivered should be prescribed before starting each session of RRT. (Not Graded) We recommend

frequent assessment of the actual delivered dose in order to adjust the prescription. (1B)

5.8.2: Provide RRT to achieve the goals of electrolyte, acid-base, solute, and fluid balance that will meet the patient’s needs. (Not

Graded )

5.8.3: We recommend delivering a Kt/V of 3.9 per week when using intermittent or extended RRT in AKI. (1A)

5.8.4: We recommend delivering an effluent volume of 20-25 mL/kg/h for CRRT in AKI (1A). This will usually require a higher

prescription of effluent volume. (Not Graded)

Abbreviations: AKI, acute kidney injury; BUN, blood urea nitrogen; CRRT, continuous renal replacement t

aki guideline

Documents